Although the phenomenon of social familiarity-induced anxiolysis (SoFiA) has been well documented for decades, and is the basis of most behavioral therapy techniques, the neural mechanisms that underlie it are still poorly understood. This lack of knowledge regarding the mechanisms that regulate a basic principle governing social behavior severely limits our ability to advance social behavior research. Our long-term goal is to improve mental healthcare by discovering the mechanisms that regulate psychosocial behaviors and enabling development of improved treatment strategies. The overall objective of this application is to elucidate the fundamental mechanisms by which social familiarity becomes encoded as a safety cue and the mechanisms that suppress anxiety-like responses in its presence. Our central hypothesis is that the infralimbic cortex is the pivotal locus within the neural circuit that regulates the acquisition and expression of social familiarity induced reductions in anxiety. The proposed research will define the neural circuitry and the key neural mechanisms that mediate acquisition of SoFiA and will identify the pivotal neural pathways that induce the anxiolytic response to social familiarity. This contribution is significan because it will directly impact 2 NIMH priorities by (1) increasing our understanding of the fundamental mechanisms of complex social behavior and (2) elucidating the neural circuitry regulating the RDoC domain of Systems for Social Processes, specifically the construct Affiliation and Attachment. Thus providing key insights that can be readily translated into clinical research paradigms and move towards advancing mental health care. Aim 1: Identify the neural circuitry critical for social familiarity-induced anxiolysis. Using cFos expression, we will identify candidate neural structures involved in the acquisition and expression of SoFiA. The neural connections within these structures that are pivotal to the acquisition of SoFiA will be determined using in vivo optogenetic techniques to transiently inactivate projections into the IL from select candidate nuclei and determine which block SoFiA acquisition. Aim 2: Elucidate neural plasticity mechanisms of social familiarity-induced anxiolysis. Using the highly innovative NARG (Neural Activity Related Gene) and glutamate- and plasticity-related genes expression array we will gain insights into the loci of neuronal plasticity that contributes to SoFiA acquisition. Site directed pharmacology within the IL during the SoFiA acquisition phase will determine the role of specific glutamate receptors in SoFiA acquisition. Aim 3: Identify the pivotal neural connections that modulate anxiolysis in response to social familiarity. Neural pathways that are necessary and sufficient for expression of SoFiA will be identified using in vivo optogenetic techniques specifically targeting IL projections in key limbic structures during behavioral assays.